NF-kB is a transcription factor that regulates expression of factors critical to inflammation and cell survival, and thus plays a central role in multiple human diseases. NF-kB is regulated by IkB which sequesters the transcription factor in the cytoplasm. In response to a variety of stimuli, IkB is transiently degraded allowing translocation of NF-kB into the nucleus where it activates expression of a wide array of genes. Interestingly, the genes that NF-kB activates are often specific to the cell type and stimulus in question and our current knowledge of this pathway cannot fully account for these differential effects. We recently discovered a novel family of conserved factors that inhibit NF-kB, called COMMD proteins. COMMD1, the prototype of this family, acts in the nucleus where it is recruited to chromatin and promotes the release of promoter-bound NF-kB. Our most recent data indicate that COMMD1 mediates ubiquitination and proteasomal degradation of NF-kB subunits through a multimeric ubiquitin ligase known as ECS-SOCS1. Since ubiquitination of NF-kB has been previously linked to its release from promoter sites, COMMD1-mediated ubiquitination provides a mechanism for its effects on chromatin-bound NF-kB. In addition, while IkB is broadly inhibitory, individual COMMDs have effects on specific subsets of kB-responsive genes. We speculate that COMMD proteins function at specific gene targets by recruiting a ubiquitin ligase to locally inhibit NF-kB. Therefore, we hypothesize that the multi-member COMMD family plays a critical role in providing specificity to the NF-kB pathway. We believe that through their effects on NF-kB, COMMDs are likely involved in inflammation and oncogenesis. The overall goals of this project are: to determine the mechanism by which COMMD1 mediates NF-kB ubiquitination (AIM 1), to elucidate the mechanisms that control the activity of COMMD1 (AIM 2) and to investigate the differential effects of COMMD proteins on gene regulation (AIM 3). Lay Description: NF-kB is a master regulator of gene expression that is responsible for turning on genes critical in inflammation. Hence, NF-kB plays a central role in diseases that have inflammation as a common feature. We have discovered a group of factors named COMMD proteins that inhibit NF-kB. The overall goal of this proposal is to understand how COMMD proteins work since their mechanism of action might provide clues to design anti-inflammatory therapies with a broad range of potential applications